Inhibition of cyclobutane pyrimidine dimer formation in epidermal p53 gene of UV-irradiated mice by alpha-tocopherol.
Mutations or alterations in the p53 gene have been observed in 50-100% of ultraviolet light (UV)-induced squamous cell carcinoma in humans and animals. Most of the mutations occurred at dipyrimidine sequences, suggesting that pyrimidine dimers in the p53 gene play a role in the pathogenesis of cutaneous squamous cell carcinoma. We previously showed that topical alpha-tocopherol prevents UV-induced skin carcinogenesis in the mouse. In the present study we asked whether topical alpha-tocopherol reduces the level of UV-induced cyclobutane pyrimidine dimers in the murine epidermal p53 gene. Mice received six dorsal applications of 25 mg each of alpha-tocopherol, on alternate days, before exposure to 500 J/m2 of UV-B irradiation. Mice were killed at selected times after irradiation. The level of dimers in the epidermal p53 gene was measured using the T4 endonuclease V assay with quantitative Southern hybridization. Topical alpha-tocopherol caused a 55% reduction in the formation of cyclobutane pyrimidine dimers in the epidermal p53 gene. The rate of reduction of pyrimidine dimers between 1 and 10 hours after irradiation was similar in UV-irradiated mice, regardless of alpha-tocopherol treatment. Therefore, the lower level of cyclobutane pyrimidine dimers in UV-irradiated mice treated with alpha-tocopherol than in control UV-irradiated mice resulted from the prevention of formation of the dimers, and not from enhanced repair of these lesions. Our results indicate that alpha-tocopherol acts as an effective sunscreen in vivo, preventing the formation of premutagenic DNA lesions in a gene known to be important in skin carcinogenesis.
Chen
W
W
Department of Radiation Oncology, College of Medicine, University of Arizona, Tucson 85724, USA.
Barthelman
M
M
Martinez
J
J
Alberts
D
D
Gensler
H L
HL
D000279:Administration, Cutaneous; D000818:Animals; D015139:Blotting, Southern; D005260:Female; D016158:Genes, p53 / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000517:prevention & control; D011740:Pyrimidine Dimers / Q000096:biosynthesis* / Q000235:genetics / Q000528:radiation effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000517:prevention & control; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects; D014810:Vitamin E / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D011740:Pyrimidine Dimers; D014810:Vitamin E